Cardiovasculardisease(CVD)istheleadingcauseofdeathintheUSA.Increasedlevelsofreactiveoxygen species (ROS) are often associated with microvascular pathology in CVD, causing endothelial dysfunction andcoronaryarterydiseaseandleadingtomyocardialischemiaandinfarction(MI).However,failureoflarge clinical trials using antioxidants in patients with CVD, challenges the prevailing view that ROS production is damaging to the microvasculature. The overarching hypothesis put forth in this proposal is that EC NOX- derived ROS is beneficial for revascularization immediately following myocardial ischemia but becomes detrimentaluponovertheLTduetoincreaseinmitochondrialROS.Thetherapeuticbenefitofinterveningon ROS level is best realized by specific down regulation of mito-ROS in ECs that have been exposed to LT increaseinNOX-ROSsuchasinDM.ThishypothesiswillbefullytestedinvivousingournovelEC-specific transgenic MnSOD (MnSOD-OE) animals and supported using mitochondria-specific nitroxide and nanoparticleantioxidantincoronaryvesselsfromCVDpatientswithDMundergoingcardiacsurgery. SpecificAim1:ElucidatethemolecularmechanismsbywhichSTvsLTincreaseinEC-specificNOX-ROS (NOX-OE mouse model) exert differential effects on EC function and angiogenesis and the recovery of the post-infarct ischemic myocardium. We hypothesize that whereas ST NOX-ROS increase induces AMPK?eNOS and AMPK?CPT1-mediated increase in mitochondrial fatty acid oxidation and dNTP synthesis,LTincreaseinNOX-ROSresultsinnitro-tyrosine-inducedinactivationofMnSOD,increaseinmito- ROS,decreaseinmito-membranepotentialanddNTPsynthesisleadingtoreducedECproliferation. SpecificAim2:DetermineifEC-specificMnSODoverexpressionprotectsagainstthedetrimentaleffectsof LT exposure of NOX-ROS on vessel density and cardiac functions in post-infarct ischemic myocardium. We hypothesize that SOD-OE will improve post-MI recovery of the cardiac function by reducing mito-ROS and improvingdNTPsynthesis/ECproliferationinLTNOX-OEanimalsandinanimalswithDM.Doubletransgenic NOX-OE:SOD-OEvsNOX-OE,andSOD-OEwithDMwillbeexaminedforpost-MIrecovery. Specific Aim 3: Elucidate the effects of mitochondrial-targeted nitroxide antioxidant and SOD biomimetic nanoparticles on post-infarct vessel density and recovery of cardiac function in mice and on chronic myocardialischemiainlargeanimals(swine)withmetabolicsyndrome. Specific Aim 4: Determine the effects of mitochondrial-targeted nitroxide antioxidant and SOD biomimetic nanoparticlesonangiogenicpotentialofhumancoronaryvesselsfrompatientswithorwithoutDM.Coronary vessels from atrial tissues of patients (uncontrolled DM HbA1c>8.5, controlled DM HbA1c<7, and non-DM HbA1c<5.5)undergoingcardiacsurgerywillbeexamined.